Abstract

The immunoregulatory protein T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates T cell exhaustion and contributes to suppression of immune responses in both viral infections and tumors. Tim-3 blockade reverses the exhausted phenotype of CD4+ and CD8+ T cells in several chronic diseases including melanoma. Interestingly, natural killer (NK) cells constitutively express Tim-3, however, its role in modulating the function of these innate effector cells remains unclear, particularly in human disease. In this study, we compared the function of Tim-3 in NK cells from healthy donors and patients with metastatic melanoma. NK cells from the latter were functionally impaired/exhausted and Tim-3 blockade reversed this exhausted phenotype. Moreover, Tim-3 expression levels correlated with the stage of the disease and poor prognostic factors. These data indicate that Tim-3 can function as an NK cell exhaustion marker in advanced melanoma and supports the development of Tim-3-targeted therapies to restore anti-tumor immunity.